Persons with hemochromatosis constitute a plentiful and willing source of blood for transfusion. Recent changes in federal regulations have eased restrictions on the use of blood from hemochromatosis subjects for transfusion, however, no data exist to guide the performance of phlebotomy therapy in a blood donor center setting. We established and evaluated a program for treating persons with hemochromatosis in a donor center, and making their blood available for transfusion. Phlebotomy therapy was performed free of charge regardless of whether subjects met criteria for allogeneic donation. Hemoglobin of 12.5 g/dL was used as the threshold for performing phlebotomy and decreases in the MCV were used to guide the endpoints of therapy. 250 subjects were consecutively enrolled: 74% were homozygous for the C282Y mutation in the HFE gene, 77% met eligibility criteria for allogeneic donation, and 54% were previous blood donors. A median of 20 weekly or biweekly phlebotomies (range 7-99) were performed before the MCV reached the targeted endpoint of 3% below baseline, at which time the ferritin was less than 30 mcg/L and the transferrin saturation less than 30%. The median phlebotomy interval necessary to keep the MCV at this level during maintenance therapy was 10 weeks. No incident seroconversions for agents of transfusion-transmissible disease occurred during 2,440 donations. All subjects testing positive for viral agents gave a prior history of deferrable risk. As of September 2005, hemochromatosis donors were contributing 13% of the red cell units collected for allogeneic use in the NIH Clinical Center. Due to the steady contributions of NIH hemochromatosis donors, it was not necessary to postpone surgery or acquire blood from outside suppliers during periods of low inventory, at a time when regional blood supplies were at critically low levels in other hospitals. Our data demonstrate that hemochromatosis subjects can safely and significantly augment the allogeneic blood supply. Provision of phlebotomy therapy unrestricted by considerations of cost or suitability for donation can improve access to care and remove incentives for incomplete risk disclosure. Additional studies in this cohort indicate that there is a higher than expected incidence of thyroid abnormalities in hemochromatosis subjects, most commonly subclinical hypothyroidism. Thyroid function abnormalities were found in 30% of female subjects with homozygosity for the C282Y HFE mutation. Symptoms in affected patients included fatigue, depression, and anemia during therapy. Current efforts are focused on overcoming community and Red Cross Blood Center resistance to use of hemochromatosis subjects as allogeneic blood donors, on dissemination of best phlebotomy practices as exhibited in this study, on critical examination of the role of double red cell donation by apheresis in the management of HH subjects, on delineating the effect of phlebotomy therapy on arthritic symptoms, and on assessing changes in serum non-transferrin bound iron levels during therapy.